The 2.0 angstrom structure of human ferrochelatase, the terminal enzyme ofheme biosynthesis

Human ferrochelatase (E.C. 4.99.1.1) is a homodimeric (86 kDa) mitochondria l membrane-associated enzyme that catalyzes the insertion of ferrous iron i nto protoporphyrin to form heme. We have determined the 2.0 Angstrom struct ure from the single wavelength iron anomalous scattering signal. The enzyme contains two NO-sensitive and uniquely coordinated [2Fe-2S] clusters. Its membrane association is mediated in part by a 12-residue hydrophobic Lip th at also forms the entrance to the active site pocket. The positioning of hi ghly conserved residues in the active site in conjunction with previous bio chemical studies support a catalytic model that may have significance in ex plaining the enzymatic defects that lead to the human inherited disease ery thropoietic protoporphyria.